Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

Structure‐based drug development is often hampered by the lack of in vivo activity of promising compounds screened in vitro, due to low membrane permeability or poor intracellular binding selectivity. Herein, we show that ligand screening can be performed in living human cells by “intracellular protein‐observed” NMR spectroscopy, without requiring enzymatic activity measurements or other cellular assays. Quantitative binding information is obtained by fast, inexpensive ¹H NMR experiments, providing intracellular dose‐ and time‐dependent ligand binding curves, from which kinetic and thermodynamic parameters linked to cell permeability and binding affinity and selectivity are obtained. The approach was applied to carbonic anhydrase and, in principle, can be extended to any NMR‐observable intracellular target. The results obtained are directly related to the potency of candidate drugs, that is, the required dose. The application of this approach at an early stage of the drug design pipeline could greatly increase the low success rate of modern drug development.     

In Vivo Imaging of the Tumor‐Associated Enzyme NCEH1 with a Covalent PET Probe

Herein, we report the development of an ¹⁸F‐labeled, activity‐based small‐molecule probe targeting the cancer‐associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile ¹⁸F radionuclide incorporation required for PET imaging. The resulting molecule, [¹⁸F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000‐fold selectivity relative to other serine hydrolases. [¹⁸F]JW199 displays rapid, NCEH1‐dependent accumulation in mouse tissues. Finally, we demonstrate that [¹⁸F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple‐negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis.     

Viscoelastic flow in a two-dimensional collapsible channel

We compute the flow of three viscoelastic fluids (Oldroyd-B, FENE-P, and Owens blood model) in a two-dimensional channel partly bounded by a tensioned membrane, a benchmark geometry for fluid–structure interactions. The predicted flow patterns are compared to those of a Newtonian liquid. We find that computations fail beyond a limiting Weissenberg number. Flow fields and membrane shape differ significantly because of the different degree of shear thinning and molecular extensibility underlying the three different microstructural models.     

Beta-functionalised polythiophenes as microelectrode modifiers in low conductive media

A study on polythiophene coated microelectrodes is reported, the goal being that of checking the capability of these electrochemical systems to work in low conductive media. The possibility of electrochemically p-doping the polymer in the presence of very low concentrations or even in the absence of supporting electrolyte in the solution is ascertained, opening the way to the use of similar systems in pure solvent media. This result is obtained in such conditions that the presence of residual charges--and corresponding counterions--trapped inside the film coating can be reasonably hypothesised.     

Exchange interactions and spin wave theory

La Rivista del Nuovo Cimento (1971-1977) -     

Magnetic and structural properties of nanocomposite Co-Ni-Cr-Al-Y-N thin films

The relation between structural and magnetic properties of Co-Ni-Cr-Al-Y-N thin films deposited by reactive r.f. magnetron sputtering was investigated. A marked change in the magnetic behaviour of the films with the different nitrogen partial pressure in the Ar/N₂ deposition atmosphere was observed and qualitatively explained in correlation with the phase composition. The nanocrystalline metal solid-solution obtained at low N₂ content and the nanocrystalline nitride/amorphous composite obtained at high N₂ content are not magnetic, whereas the amorphous phase produced for intermediate N₂ pressures behaves like a ferromagnetic semi-permanent material. The results demonstrate the possibility of modulating the magnetic properties of r.f. magnetron sputtered Co-Ni-Cr-Al-Y-N thin films, thus opening a new route for magnetic multilayer deposition. PACS 68.55.-a; 75.70.Ak; 75.75.+a; 85.70.-w     

Hysteresis of charge tunneling in assemblies of carboxylic acid-modified gold nanoparticles

We report on charge transport measurements through laterally contacted assemblies of Au nanoparticles capped with 11-mercaptoundecanoic acid ligands. Both alternating- and direct-current data indicate that although the nanoparticles behave as electrically isolated metallic islands, there is a significant influence from the nanoparticle environment, indicating the existence of a slow reorganization process linked to charge transport. On the basis of the observation of temperature-dependent hysteresis of charge tunneling, we propose that this process is due to proton transfer between the carboxylic acid tails of the ligands.